Introduction and Objective: Obesity is a leading driver of cardiometabolic disease that affects more than 130 million people in the United States. Although current obesity pharmacotherapies can reduce body weight by up to 25% in clinical trials, evidence from bariatric surgery cohorts demonstrates that weight loss exceeding 30% yields even greater metabolic benefits. This highlights the need for next-generation treatments capable of achieving greater efficacy in order to provide greater metabolic disease resolution, particularly for patients with severe disease burden Methods: We have developed VRX-0075, a long-acting quintuple agonist targeting the GLP-1, GIP, glucagon, amylin, and calcitonin receptors. Results: VRX-0075 exhibits in vitro potency comparable to retatrutide at the GLP-1, GIP, and glucagon receptors, while matching the potency of cagrilintide at the amylin and calcitonin receptors. In obese rats, VRX-0075 demonstrates a half-life approximately 50% longer than semaglutide, suggesting that it is suitable for weekly dosing in humans. Importantly, VRX-0075 induces significantly greater weight loss in obese rats than retatrutide at the same molar dose with no observable toxicology findings in a non-regulatory setting. Conclusion: Collectively, these findings support VRX-0075 as a development candidate for achieving best-in-class cardiometabolic disease resolution in patients with obesity. Disclosure J. Douros: Research Support; Current; Eli Lilly and Company. S. Mowery: Research Support; Current; Eli Lilly and Company. M. Kalwat: Research Support; Current; Eli Lilly and Company. Stock/Shareholder; Current; Pfizer Inc. S. Dodson: None. R. Shrinivasan: None. P.J. Knerr: Stock/Shareholder; Current; Novo Nordisk. Research Support; Current; Eli Lilly and Company. Stock/Shareholder; Current; Volari Therapeutics.
DOUROS et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: